RESUMO
We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/farmacologia , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Sistema Biliar/metabolismo , Desenho de Fármacos , Concentração Inibidora 50 , Isomerismo , Fenilalanina/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/química , Fenilalanina/farmacologia , Triazinas/química , Triazinas/farmacologia , Fenilalanina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
The SAR studies to optimise both potency and rate of clearance in the rat for a series of pyrimidine and pyridine based VLA-4 antagonists are described.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/química , Fenilalanina/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Fenilalanina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.
